TGFβ1 induces in-vitro and ex-vivo angiogenesis through VEGF production in human ovarian follicular fluid-derived granulosa cells during in-vitro fertilization cycle

[Display omitted] •TGFβ1 is found in IVF patients’ follicular fluid (FF) and its level is sufficient to be physiologically active.•TGFβ1 causes angiogenesis via follicular granulosa cells (GCs)-mediated VEGF induction and secretion.•The cellular signaling pathways for VEGF production in GCs are TGFβ...

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Bibliographic Details
Published in:Journal of reproductive immunology 2021-06, Vol.145, p.103311-103311, Article 103311
Main Authors: Lai, Tsung-Hsuan, Chen, Hsuan-Ting, Wu, Wen-Bin
Format: Article
Language:English
Subjects:
Angiogenesis
follicular fluid
Folliculogenesis
In-vitro fertilization
IVF
Neovascularization
TGF β
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Summary:[Display omitted] •TGFβ1 is found in IVF patients’ follicular fluid (FF) and its level is sufficient to be physiologically active.•TGFβ1 causes angiogenesis via follicular granulosa cells (GCs)-mediated VEGF induction and secretion.•The cellular signaling pathways for VEGF production in GCs are TGFβR, Smad2/3, PI3 K/Akt, and JNK1/2.•The FF TGFβ1, GCs, and VEGF act in concert to cause follicular angiogenesis in human IVF cycle. A growing body of evidence indicates that angiogenesis in folliculogenesis contributes to oocyte developmental competence in natural and in-vitro fertilization (IVF) cycle of animals. Among the known angiogenic factors, vascular endothelial growth factor (VEGF) has an important role involved in angiogenesis. However, its expression level and regulatory mechanism in ovarian follicular fluid (FF) in patients undergoing IVF with controlled ovarian stimulation (COS) remains to be explored. In this study, the primary cultured human ovarian follicular granulosa cells (GCs) were prepared from FF and their identity was characterized by the presence of the GC specific markers. The transforming growth factor β1 (TGFβ1) was found to induce a significant increase in VEGF mRNA level and protein expression/secretion in GCs. In line with these observations, TGFβ1 could be detected in the ovarian FF, ranging from about 400 to 2000 pg/mL among three IVF patient groups with different patient’s serum Anti-Müllerian hormone level. The cellular signaling analysis revealed that TGFβ1 induced VEGF production through TGFβ receptor (TGFβR), Smad2/3, PI3 K/AKT, and JNK1/2-related signaling pathways. Finally, in a functional study, the TGFβ1-primed GC VEGF secretion promoted in-vitro angiogenesis in vascular endothelial cells and ex-vivo vessel sprouting in aortic ring. Taken together, we demonstrated here that TGFβ1 expressed in ovarian FF is an inducer for promoting VEGF production in follicular GCs through TGFβR-mediated signaling pathways and the released VEGF subsequently leads to angiogenesis. This possibly contributes to oocyte developmental competence in folliculogenesis of IVF patients with a COS protocol.
ISSN:0165-0378
1872-7603
DOI:10.1016/j.jri.2021.103311